The leading cause of congestive heart failure (CHF) is post-myocardial infarction (MI) cardiomyopathy, which results from pathologic remodeling of viable heart muscle after loss of infarcted tissue. Some pharmacologic interventions slow declines in cardiac function, but there remain no means to halt the progression of post-MI remodeling to end-stage failure. Molecular and cellular interventions in cardiac function are therefore viewed as an important new horizon. Cardiac hypertrophy can be physiologic, a stable and reversible process observed in exercise and pregnancy, or pathologic, an irreversible response to stresses such as hypertension and MI that degenerates to dilated cardiomyopathy. Many molecular pathways are known to be active during pathologic and, to a lesser degree, physiologic hypertrophy, but it is not clear how these distinct responses are regulated, nor how differing stresses are translated into different outcomes. During the course of the current R01, we discovered that loss of alpha adrenergic receptors, an important source of physiologic hypertrophic signaling, leads to an increase, rather than a decrease, in post-MI hypertrophy. This increase, however, was characterized by pathologic hypertrophy, suggesting a dynamic balance between physiologic and pathologic hypertrophy, even in response to pathologic stresses. If a loss of the former can increase the latter, therapeutic instigation of a heightened level of physiologic hypertrophy may lessen the induction of pathologic hypertrophy. In the proposed studies, we will test this translational hypothesis utilizing a new and unique genetic model of regulatable MEK1-ERK1/2 signaling. Our first Specific Aim will involve induction of physiologic hypertrophic MEK1-ERK1/2 signaling at critical time points after MI to assess a resulting shift away from pathologic hypertrophy during post-MI remodeling. The second Aim will focus on a careful dissection of the downstream molecular effectors of this change, and elucidate specific pathways by which the myocardium is shifted toward physiologic or pathologic hypertrophy. In the third Specific Aim, we will evaluate whether these observations are specific to post-MI pathophysiology or whether they represent a generalizable, novel understanding of cardiac hypertrophy by applying the most successful strategy and analyses from Aims 1 and 2 to an alternative form of pathologic hypertrophy observed after experimental aortic constriction. Finally, our new model of regulatable MEK1-ERK1/2 upregulation will allow us to combine the induction of physiologic hypertrophy with surgical ventricular reconstruction, a necessary adjunct to any molecular therapy applied to severely misshapen hearts in the later stages of cardiomyopathy.